This application is a 371 of PCT/JP01/00473 filed 25 Jan. 2001.
The present invention relates to a benzene-fused heteroring derivative.
Particularly, the present invention relates to;
1) a benzene-fused heteroring derivative of formula (I) 
xe2x80x83wherein all symbols have the same meanings as hereinafter, and a non-toxic salt thereof,
2) a method for the preparation thereof and
3) a pharmaceutical agent comprising the benzene-fused heteroring derivative and non-toxic salt thereof as active ingredient.
Cysteine protease is a generic name of proteases which have a cysteine residue in the activity center and catalyze protein degradation thereat. In animal cells, a large number of cysteine proteases are known; for example, cathepsin family, calpain family, caspase-1, etc. Cysteine protease exists in various kinds of cells extensively and plays a basic and essential role in the homeostasis, such as conversion (processing) of precursor protein into its active form and degradation of proteins which have become out of use, etc. Until now, its physiological effects are being vigorously studied, and as the studies progress and characteristics of the enzymes are revealed, cysteine protease came to be taken as a cause of really various kinds of diseases.
It is revealed that cathepsin S (See J. Immunol., 161, 2731 (1998)) and cathepsin L (See J. Exp. Med., 183, 1331 (1996)) play a role in processing of major histocompatibility antigen class-II in antigen presenting cells which play an important role in the early stage of immune responses. In an experimental inflammatory response model induced by antigens, a specific inhibitor of cathepsin S showed an inhibitory effect (see J. Clin. Invest., 101, 2351 (1998)). It is also reported that in a leishmania-infected immune response model cathepsin B inhibitor inhibited an immune response and by means of this effect it inhibited the proliferation of protozoans (See J. Immunol., 161, 2120 (1998)). In vitro, a result is given that a calpain inhibitor and a cysteine protease inhibitor E-64 inhibited apoptosis which is induced by stimuli on T cell receptors (see J. Exp. Med., 178, 1693 (1993)). Therefore, it is conceivable that cysteine protease is much concerned with the progress of immune responses.
It is speculated that caspase-1 or a cysteine protease similar thereto occupies an important position in the mechanism of cell death including apoptosis. Therefore it is expected for a cysteine protease inhibitor to be used as an agent for the prophylaxis and/or treatment of those diseases concerning apoptosis, such as infectious diseases, deterioration or sthenia of immune function and brain function, tumors, etc. Diseases concerning apoptosis are, acquired immune deficiency syndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia, hairy cell leukemia, spondylopathy, respiratory apparatus disorder, arthitis, HIV or HTLV-1 related diseases such as uveitis, virus-related diseases such as hepatitis C, cancer, collagenosis (systemic lupus erythematosus, rheumatoid arthritis, etc.), autoimmune diseases (ulcerative colitis, Sjogren""s syndrome, primary biliary cirrhosis, spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, insulin dependent (type I) diabetes, etc.), diseases accompanied by thrombocytopenia (osteomyelodysplasia syndrome, periodic thrombocytopenia, aplastic anemia, spontaneous thrombocytopenia, disseminated intravascular coagulation (DIC), etc.), hepatic diseases such as viral hepatitis (type C, A, B, F, etc.) or hepatitis medicamentosus and cirrhosis, dementia (Alzheimer""s diseases, Alzheimer""s senile dementia, etc.), cerebrovascular injury, nerve degeneration diseases, adult acute respiratory distress syndrome, infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma, arteriosclerosis, all kinds of lusus naturae, nephropathy, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy, etc.
Moreover, caspase-1 is concerned with various inflammatory diseases and those diseases caused by immune disorders, by means of interleukin-1xcex2 (IL-1xcex2) production. A lot of diseases are shown to be involved with caspase-1 including inflammatory diseases and autoimmune diseases listed below; inflammatory bowel diseases such as ulcerative colitis, insulin-dependent (type-I) diabetes, autoimmune thyroid diseases, infectious diseases, rejection of an organ transplantation, graft versus host diseases, psoriasis, periodontitis (above, see N. Eng. J. Med., 328, 106 (1993)), pancreatitis (see J. Interferon Cytokine Res., 17, 113 (1997)), hepatitis (see J. Leuko. Biol., 58, 90 (1995)), glomerulonephritis (see Kidney Int., 47, 1303 (1995)), endocarditis (see Infect. Immun., 64, 1638 (1996)), myocarditis (see Br. Heart J., 72, 561 (1995)), systemic lupus erythematosus (see Br. J. Rheumatol., 34, 107 (1995)), Hashimoto""s diseases (see Autoimmunity, 16, 141 (1993)), etc.), etc. Experimentally, it is reported that in liver injury model induced by lipopolysaccharide and D-galactosamine, a caspase-1 inhibitor depressed the symptoms, and it is expected that a caspase inhibitor shows an effect in sepsis, ischemic reperfusion and hepatitis gravis (see Am. J. Respir. Crit. Care Med., 159, 1308 (1999)).
It is also shown that cysteine protease is concerned with rheumatoid arthritis. IL-1xcex2 is shown to be concerned with this disease (see Arthritis Rheum., 39, 1092 (1996)), and in addition, as autoantibody toward calpastatin (endogenous calpain inhibitor) was found in the serum of the patients, it is considered that increase of calpain activity leads to the cause of diseases.
It is also known that cysteine protease causes a disease symptom by decomposing various proteins which compose the organism.
It is reported that cathepsin B plays a role in decomposing muscular protein in the chronic phase of sepsis (see J. Clin. Invest., 97, 1610 (1996)), and in decomposing muscular protein in myodystrophy model (see Biochem. J., 288, 643 (1992)). And it is also reported that calpain decomposes the myocyte cells protein of myodystrophy patients (see J. Biol. Chem., 270, 10909 (1995)).
In the ischemic reperfusion model, a result is given that calpain causes degeneration of brain tissues by means of degradation of protein kinase C-xcex2 (see J. Neurochem., 72, 2556 (1999)) and that a cathepsin B inhibitor inhibits nerve injury (see Eur. J. Neurosci., 10, 1723 (1998)).
In the brain ischemic model, it is known that the degradation of spectrin by calpain causes a damage and function disorder in the neurocyte (see Brain Res., 790, 1(1998)) and it is reported that an IL-1xcex2 receptor antagonist relieved the symptoms (see Brain Res. Bull., 29, 243 (1992)).
In myocardial ischemic model it is confirmed that cathepsin B activity increases in the lesion (see Biochem. Med. Metab. Biol., 45, 6 (1991)).
In the experiment utilizing ischemic liver injury model, it proved that necrosis and apoptosis of hepacyte were induced by means of protein-decomposing activity of calpain (see Gastroenterology, 116, 168 (1999)).
Besides, it is known that calpain causes cornea turbid in cataract by means of degradation of crystalline (see Biol. Chem., 268, 137 (1993)) and that in the lesion of contracted gut mucosa model it was confirmed that the activity of cathepsin B, H and L increased (see JPEN. J. Parenter. Enteral. Nutr., 19, 187 (1995)) and it is shown that cysteine protease is a cause of the diseases resulting from such protein degradation.
It has been revealed that cysteine protease is concerned with systemic disorders of organs and tissues by shock.
It is shown that IL-1xcex2 is concerned with septic shock and systemic inflammatory response syndrome (see Igakuno Ayumi, 169, 850 (1994)) and besides, it is reported that in endotoxin shock model induced by lipopolysaccharide, a calpain inhibitor prevented circulatory system disorder, disorders of liver and pancreas and acidosis by means of inhibitory effect of activation of nuclear factor KB (see Br. J. Pharmacol., 121, 695 (1997)).
Since it is reported that calpain is concerned with platelet coagulation process and a calpain inhibitor prevented the coagulation of platelets (see Am. J. Physiol., 259, C862 (1990)), it is conceivable that a cysteine protease inhibitor is useful for the disorder by blood coagulation. From the fact that calpain activity increased in the serum of the patients of purpura (thrombocytopenia) resulting from marrow transplantation, it is conceivable that calpain is concerned with the actual disease symptoms (see Bone Marrow Transplant., 24, 641 (1999)). Caspase-1 inhibitor inhibited the apoptosis of blood vessel endothelial cells, which is seen in the early phase of purpura (thrombocytopenia) and is thought to be important for the progression of the pathology afterwards (see Am. J. Hematol., 59, 279 (1998)), so it is expected that a cysteine protease inhibitor makes effect on purpura and hemolytic uremic syndrome.
The effect of cysteine protease and its inhibitor is being investigated in the field of cancer and metastasis of cancer.
Since the proliferations of pancreas cancer cells (see Cancer Res., 59, 4551 (1999)) and acute myeloid leukemia cells (see Clin. Lab. Haematol., 21, 173 (1999)) were inhibited by an inhibitor or receptor antagonist of caspase-1, it is expected that caspase-1 activity is essential for the process of proliferation of tumor cells, and that an inhibitor thereof is effective for these cancers. Cathepsin B activity increased in colon cancer metastasis model (see Clin. Exp. Metastasis, 16, 159 (1998)). Cathepsin K protein expression was recognized in human breast cancer cells and the relationship of cathepsin K and bone metastasis is shown (Cancer Res., 57, 5386 (1997)). Also, a calpain inhibitor inhibited migaration of the cells and it implied the possibility that calpain inhibition may inhibit metastasis of cancer (J. Biochem., 272, 32719 (1997)). From these, a cysteine protease inhibitor is presumed to show an inhibitory effect on the metastasis of various malignant tumors.
As to AIDS (see AIDS, 10, 1349 (1996)) and AIDS-related complex (ARC) (see Arch. Immunol. Ther. Exp. (Warsz), 41, 147 (1993)), it is shown that IL-1 is concerned with the progress of symptoms, so it is conceivable that cysteine protease inhibition leads to an effective therapy of AIDS and its complication.
Some parasites have cysteine protease activity in their body. Cysteine protease in the phagosome of malaria protozoan is an essential enzyme for supplying nutrition of the parasites. A result is given that the inhibitor of cysteine protease shows an inhibitory effect of the proliferation of the protozoan (see Blood, 87, 4448 (1996)). Thus, it is possible to apply the inhibitor of cysteine protease to malaria.
In Alzheimer-type dementia, it is said that adhesion of non-physiological protein called amyloid to brain is deeply involved with nervous function disorders. Cysteine protease has an activity of generating amyloid by decomposing its precursor protein. Clinically, it is shown that cathepsin B is an enzyme that possesses a processing activity of amyloid proteins in the brains of Alzheimer-type dementia patients (see Biochem. Biophys. Res. Commun., 177, 377 (1991)). Also, expressions of cathepsin B protein (see Virchows Arch. A. Pathol. Anat. Histpathol., 423, 185 (1993)), cathepsin S protein (see Am. J. Pathol., 146, 848 (1995)) and calpain protein (see Proc. Natl. Acad. Sci. USA, 90, 2628 (1993)) and increase of caspase-1 activity (see J. Neuropathol. Exp. Neurol., 58, 582 (1999)) were confirmed in the brain lesions. Besides, by the fact that calpain is concerned with the formation of paired helical filaments which accumulate in Alzheimer dementia patients and production of protein kinase C which stabilizes the protein by phosphorylation (see J. Neurochem., 66, 1539 (1996)) and by the knowledge that caspase is concerned with neurocyte death by xcex2 amyloid protein adhesion (see Exp. Cell Res., 234, 507 (1997)), it is implied that cysteine protease is concerned with the disease symptoms.
As to Huntington""s chorea, cathepsin H activity increased in the patient""s brain (see J. Neurol. Sci., 131, 65 (1995)), and the ratio of activated form of calpain increased (see J. Neurosci., 48, 181 (1997)). In Parkinson""s diseases, the increase of expression of m-calpain was recognized in the mesencephalon of the patients (see Neuroscience, 73, 979 (1996)) and IL-1xcex2 protein was expressed in brain (see Neurosci. Let., 202, 17 (1995)). Therefore, it is speculated that cysteine protease is concerned with the genesis and progress of these diseases.
Besides, in the central nervous system, spectrin degradation by calpain is found in the process of injury on neurocyte observed in the traumatic brain injury model (see J. Neuropathol. Exp. Neurol., 58, 365 (1999)).
In spinal cord injured model it was recognized that in glia cells calpain messenger RNA increased and its activity increased in the lesion and the possibility was shown that calpain had much to do with the degeneration of myelin and actin after injury (see Brain Res., 816, 375 (1999)). And IL-1xcex2 was shown to be concerned with the genesis of multiple sclerosis (see Immunol. Today, 14, 260 (1993)). Therefore, it is conceivable that a cysteine protease inhibitor is promising as an agent for the treatment of these nerve-injuring diseases.
Normally, cathepsin S and cathepsin K do not exist in human arterial walls but it was confirmed that they expressed in arterial sclerosis lesion and they had an decomposing activity of alveolus elastica (see J. Clin. Invest., 102, 576 (1998)) and a calpain inhibitor and antisense of m-calpain inhibited the proliferation of human blood vessel smooth muscle cells and it is shown that m-calpain is concerned with the proliferation of smooth muscle (see Arteioscler. Thromb. Vssc. Biol., 18, 493 (1998)), so it is conceivable that a cysteine protease inhibitor is promising for the treatment of blood vessel lesion such as arteriosclerosis, restenosis after percutaneous transluminal coronary angioplasty (PTCA), etc.
It is reported that in liver, cathepsin B is activated in the process of injuring hepatocyte by bile acid (see J. Clin. Invest., 103, 137 (1999)) and so it is expected that a cysteine protease inhibitor is effective for cholestatic cirrhosis.
In lungs and respiratory system, it is shown that cathepsin S is an enzyme that plays a role in elastin degradation by alveolus macrophages (see J. Biol. Chem., 269, 11530 (1994)), so it is probable that cysteine protease is a cause of pulmonary emphysema. And it is also shown that lung injury (see J. Clin. Invest., 97, 963 (1996)), lung fibrosis (see Cytokine, 5, 57 (1993)) and bronchial asthma (see J. Immunol., 149, 3078 (1992)) are caused by production of IL-1xcex2 by caspase-1.
It is pointed out that cysteine protease is also concerned with diseases concerning bones and cartilages. Cathepsin K is specifically recognized in osteoclast and it has a decomposing activity against bone matrix (see J. Biol. Chem., 271, 12517 (1996)), so its inhibitor is expected to show an effect against osteoporosis, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia and osteometastasis of cancer, where pathologic bone resorption is recognized. And since IL-1xcex2 is shown to be concerned with bone resorption and cartilage degradation, and a caspase-1 inhibitor and IL-1xcex2 receptor antagonist inhibit the bone resorption and symptoms of arthritis, a caspase-1 inhibitor and IL-1xcex2 receptor antagonist are expected to be effective for arthritis (see Cytokine, 8, 377 (1996)) and osteoporosis (J. Clin. Invest., 93, 1959 (1994)). And it is reported that IL-1xcex2 is also concerned with osteoarthritis (see Life Sci., 41, 1187 (1987)).
Cysteine protease is involved with production of various hormones. Since increase of messenger RNA of cathepsin S was recognized by stimuli of thytropin on thyroid epitheliocyte strains (see J. Biol. Chem., 267, 26038 (1992)), it is conceivable that a cysteine protease inhibitor is effective for hyperthyrodism.
Since quantity and activity of cathepsin B protein increased in the gingival sulcus liquid of periodontitis patients (see J. Clin. Periodontol., 25, 34 (1998)), it is pointed out that cysteine protease is concerned with periodontitis.
Therefore, it is expected that the compound that possesses the inhibitory activity of cysteine protease is useful as an agent for the prophylaxis and/or treatment of inflammatory diseases (periodontitis, arthritis, inflammatory bowel diseases, infectious diseases, pancreatitis, hepatitis, glomerulonephritis, endocarditis, myocarditis, etc.), diseases induced by apoptosis (graft versus host diseases, rejection of an organ transplantation, acquired immune deficiency syndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia, hairy cells leukemia, spondylopathy, disorders of respiratory apparatus, arthritis, HIV or HTLV-1 related diseases such as uveitis, virus-related diseases such as hepatitis C, cancer, collagenosis (systemic lupus erythematosus, rheumatoid arthritis, etc.), ulcerative colitis, Sjxc3x6gren""s syndrome, primary biliary cirrhosis, spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, autoimmune diseases such as insulin dependent (type I) diabetes, diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome, periodic thrombocytopenia, aplastic anemia, spontaneous thrombocytopenia, disseminated intravascular coagulation (DIC), etc.), hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) or hepatitis medicamentosus and cirrhosis, dementia such as Alzheimer""s diseases and Alzheimer""s senile dementia, cerebrovascular injury, nerve degeneration diseases, adult acute respiratory distress syndrome, infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma, arteriosclerosis, all kinds of lusus naturae, nephropathy, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy, etc.), diseases induced by disorders of immune response (graft versus host diseases, rejection of an organ transplantation, allergic diseases (bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis, diseases induced by house dusts, irritable pneumonia, food allergy, etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases (insulin-dependent (type I) diabetes, systemic lupus erythematosus, Hashimoto""s diseases, multiple sclerosis, etc.), disease by degradation various proteins which compose the organism (myodystrophy, cataract, periodontitis, hepatocyte disease by bile acid such as cholestatic cirrhosis, etc.), decomposition of alveolus elastica such as pulmonary emphysema, ischemic diseases (brain ischemia, brain disorders (encephalopathy) by ischemic reperfusion, myocardial infarction, ischemic hepatopathy, etc.), shock (septic shock, systemic inflammatory response syndrome, endotoxin shock, acidosis, etc.), circulatory system disorders (arteriosclerosis, restenosis after percutaneous transluminal coronary angioplasty (PTCA), etc.)), blood coagulation disorders (thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignant tumor, acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC), parasitic diseases such as malaria, nerve degenerative diseases (Alzheimer-type dementia, Huntington""s chorea, Parkinson""s diseases, multiple sclerosis, traumatic encephalopathy, traumatic spondylopathy, etc.), pulmopathy such as lung fibrosis, bone resorption diseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis, hypercalcemia, osteometastasis of cancer, etc.), endocrinesthenia such as hyperthyroidism.
On the other hand, what is the most important for inhibitors in inhibiting the activity of proteases is, the special reaction site which interacts with the amino acid residue that is the activity center of proteases. The surrounding structure of the reaction sites are represented by - - - P3P2P1-P1xe2x80x2P2xe2x80x2P3xe2x80x2- - - , centering peptide binding (P1-P1xe2x80x2) of the reaction site, and at P1 site there exist amino acid residues fitting the substance specificity of proteases which the inhibitors aim. Some reaction sites against cysteine proteases are known, for Example, in the specification of WO99/54317, the followings are described;
P1 position against calpain I, II (norvaline, phenylalanine, etc.),
P1 position against calpain I (arginine, lysine, tyrosine, valine, etc.),
P1 position against papain (homophenylalanine, arginine, etc.),
P1 position against cathepsin B (homophenylalanine, phenylalanine, tyrosine, etc.),
P1 position against cathepsin S (valine, norleucine, phenylalanine, etc.),
P1 position against cathepsin L (homophenylalanine, lysine, etc.),
P1 position against cathepsin K (arginine, homophenylalanine, leucine, etc.),
P1 position against caspase (aspartic acid).
On the other hand, in the specification of JP-A-6-192199, it is disclosed that a ketone derivative of formula (A) is effective as a thiol protease inhibitor, 
wherein R1A is hydrogen, R10Axe2x80x94COxe2x80x94, R10Axe2x80x94OCOxe2x80x94, R10Axe2x80x94SO2xe2x80x94 or R10Axe2x80x94NHCOxe2x80x94,
(1) when AA is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2, R9A is C6-C14 aryl optionally containing substituent(s) or xe2x80x94(CH2)mAxe2x80x94XA, wherein XA is hydrogen, hydroxy, C1-C5 alkylthio, C2-C6 alkoxycarbonylamino, heterocycle residue optionally containing substituent(s), amino, C1-C5 monoalkylamino, C2-C10 dialkylamino, C2-6 acylamino, halogen, C1-C5 alkoxy, C6-C14 aryl optionally containing substituent(s) or C6-C14 aryloxy optionally containing substituent(s), and mA is an integer of 0 or 1 to 15,
(2) when AA is xe2x80x94Oxe2x80x94, R9A is hydrogen or xe2x80x94(CH2)IAxe2x80x94XA, wherein IA is an integer of 1 to 15,
(3) when AA is xe2x80x94NR11Axe2x80x94, R9A is C6-C14 aryl optionally containing substituent(s), xe2x80x94(CH2)mAxe2x80x94XA, R9A and R11A are taken together to form an N-containing heteroring optionally containing substituent(s) (the essential parts are extracted to explain substituents).
And in the specification of JP-A-7-70058, it is disclosed that xcex1-aminoketone derivative of formula (B) 
or its pharmaceutically acceptable salt shows a strong inhibitory activity against thiol protease, wherein R1B is hydrogen, R4Bxe2x80x94Oxe2x80x94C(O)xe2x80x94 or R4Bxe2x80x94C(O)xe2x80x94, wherein R4B is C1-C20 alkyl optionally containing a substituent or more selected from C3-C15 cycloalkyl, C6-C14 aryl optionally containing substituent(s), heterocycle residue optionally containing substituent(s), C3-C15 cycloalkyloxy, C6-C14 aryloxy optionally containing substituent(s), aralkyloxy optionally containing substituent and C6-C14 arylthio optionally containing substituent(s); C2-C10 alkenyl optionally substituted with C6-C14 aryl optionally containing substituent(s); C6-C14 aryl optionally containing substituent(s) or heterocycle residue optionally containing substituent), R2B and R3B are each independently, hydrogen or C1-C20 alkyl optionally containing a substituent, 
is heterocycle residue optionally containing a substituent, nB is 0 or 1, mB is an integer of 1 to 5.
The present inventors have energetically investigated to find out such compounds that have cysteine protease inhibitory activity and found that the benzene-fused heteroring derivative of formula (I) of the present invention accomplishes the purpose.
The benzene-fused heteroring of formula (I) of the present invention is not known at all as a cysteine protease inhibitor at all.
The present invention relates to
(1) an oxadiazole derivative of formula (I), 
wherein R is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA,
(iv) C1-8 alkyl substituted with a group selected from halogen atom, CycA, nitro, CF3 and cyano, 
CycA is a C3-15 mono-, bi- or tri-cyclic carboring or a mono-, bi- or tri-cyclic 3-15 membered heteroring comprising 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur;
R16 is
(1) C1-8 alkyl,
(2) C2-8 alkenyl,
(3) C2-8 alkynyl,
(4) CycA or
(5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with a group selected from halogen atom, nitro, CF3, cyano, CycA, NR18R19 and xe2x80x94NHC(O)-CycA;
R17, R18 and R19 each independently represents hydrogen or C1-4 alkyl,
AA1 is
(i) a single bond, or 
wherein R1 and R2 are the same or different to represent
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA or
(iv) C1-8 alkyl substituted with 1-5 of group selected from the following (1) to (8):
(1) xe2x80x94NR2 1R2 2,
(2) xe2x80x94O2 3,
(3) xe2x80x94SR2 4,
(4) xe2x80x94COR2 5,
(5) xe2x80x94NR2 6CONR2 1R2 2,
(6) guanidino,
(7) CycA,
(8) xe2x80x94NR2 6SO2R2 1; or
R1 and R2 are taken together to form C2-8 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR20xe2x80x94 and the alkylene may be substituted with xe2x80x94NR21R22 or xe2x80x94OR23,
R20 is hydrogen, C1-4 alkyl, xe2x80x94COOxe2x80x94(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R21, R22, R23, R24 and R26 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R25 is C1-4 alkyl, phenyl, xe2x80x94NR21R22, wherein all symbols have the same meaning as above, xe2x80x94OR23, wherein R23 is the same meaning as above, or C1-4 alkyl substituted with phenyl,
R3 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or
R3 is taken together with R1 to form C2-6 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR20xe2x80x94 and the alkylene may be substituted with xe2x80x94NR21R22 or xe2x80x94OR23, or when AA1 is 
AA1 and R may be taken together to form 
is a 5-12 membered mono- or bi-cyclic heteroring and the other symbols are the same meanings as above,
AA2 is
(i) a single bond, 
wherein R4 and R5 are the same or different to represent
(1) hydrogen,
(2) C1-8 alkyl,
(3) CycA or
(4) C1-8 alkyl substituted with 1-5 of group selected from the following (a) to (h):
(a) xe2x80x94NR4 1R4 2,
(b) xe2x80x94OR4 3,
(c) xe2x80x94SR4 4,
(d) xe2x80x94COR4 5,
(e) xe2x80x94NR4 6CONR4 1R4 2,
(f) guanidino,
(g) CycA,
(h) xe2x80x94NR4 6SO2R4 1; or
R4 and R5 are taken together to form C2-8 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR40xe2x80x94 and the alkylene may be substituted with xe2x80x94NR41R42 or xe2x80x94OR43,
R40 is hydrogen, C1-4 alkyl, xe2x80x94COOxe2x80x94(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R41, R42, R43, R44 and R46 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R45 is C1-4 alkyl, phenyl, xe2x80x94NR41R42, wherein all symbols are the same meaning as above, xe2x80x94OR43, wherein R43 is the same meaning as above, or C1-4 alkyl substituted with phenyl,
R6 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or
R6 is taken together with R4 to form C2-6 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR40xe2x80x94 and the alkylene may be substituted with xe2x80x94NR41R42 or xe2x80x94OR43,
R48 is hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl or when AA1 is a single bond, R48 and R may be taken together to form C2-6 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR47, wherein R47 is hydrogen or C1-4 alkyl,
CycC is a 3-17 membered mono- or bi-cyclic heteroring,
CycD is a C3-14 mono- or bi-cyclic carboring or a 3-14 membered mono- or bi-cyclic heteroring, or
AA2 and AA1 are taken together to form 
wherein
CycE is a 4-18 membered mono- or bi-cyclic heteroring,
CycF is a 5-8 membered monocyclic heteroring, and the other symbols have the same meanings as above,
R7 and R8 are the same or different to represent
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA or
(iv) C1-8 alkyl substituted with 1-5 of group selected from the following (1) to (8);
(1) xe2x80x94NR61R62,
(2) xe2x80x94OR63,
(3) xe2x80x94SR64,
(4) xe2x80x94COR65,
(5) xe2x80x94NR66CONR61R62,
(6) guanidino,
(7) CycA,
(8) xe2x80x94NR66SO2R61, or
R7 and R8 are taken together to form C2-8 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR60xe2x80x94 and the alkylene may be substituted with xe2x80x94NR61R62 or xe2x80x94OR63,
R60 is hydrogen, C1-4 alkyl, xe2x80x94COOxe2x80x94(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R61, R62, R63, R64 and R66 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R65 is C1-4 alkyl, phenyl, xe2x80x94NR61R62, wherein all symbols are the same meanings as above, xe2x80x94OR63, wherein R63 is the same meaning as above, or C1-4 alkyl substituted with phenyl,
R9 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or
R9 is taken together with R7 to form C2-6 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR60xe2x80x94 and the alkylene may be substituted with xe2x80x94NR61R62 or xe2x80x94OR63,
r is an integer of 1 to 4, 
in the ring of (i), (ii) and (iii), one saturated carbon atom or two may be replaced by
(1) oxygen,
(2) xe2x80x94S(O)sxe2x80x94 or
(3) xe2x80x94NR83xe2x80x94,
wherein s is 0 or an integer of 1 to 2,
R83 is
(a) hydrogen,
(b) C1-8 alkyl,
(c) CycA or
(d) C1-8 alkyl substituted with 1-5 of group selected from CycA, guanidino, xe2x80x94COR68, xe2x80x94NR69R70, xe2x80x94OR69, cyano and xe2x80x94P(O)(OR75)2,
R68 is C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R69 and R70 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R75 is hydrogen, C1-8 alkyl, phenyl or C1-4 alkyl substituted with 1-5 of phenyl, cyano or halogen atom and the ring of (i), (ii) and (iii) may be condensed with a C5-C8 carbon ring or a 5-8 membered heteroring containing one nitrogen atom or two, one oxygen atom and/or a sulfur atom,
q is an integer of 0 or 1 to 5,
R10 is
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) C2-8 alkynyl,
(iv) halogen atom,
(v) CycA,
(vi) xe2x80x94COR71,
(vii) xe2x80x94NR72R73,
(viii) xe2x80x94OR74 or
(ix) C1-8 alkyl substituted with 1 to 5 of groups selected from the following  less than 1 greater than  to  less than 7 greater than :
 less than 1 greater than  CycA,
 less than 2 greater than  guanidino,
 less than 3 greater than  xe2x80x94COR71,
 less than 4 greater than  xe2x80x94NR72R73,
 less than 5 greater than  xe2x80x94OR74,
 less than 6 greater than  cyano or
 less than 7 greater than  xe2x80x94P(O)(OR78)2,
wherein R82 is hydrogen, C1-8 alkyl, phenyl or C1-4 alkyl substituted with 1 to 5 of phenyl, cyano or halogen atom,
R71 is
(1) C1-8 alkyl,
(2) CycA,
(3) xe2x80x94NR72R73,
(4) xe2x80x94OR74, or
(5) C1-8 alkyl substituted with CycA;
R72 and R73 are the same or different to represent
(1) hydrogen,
(2) C1-8 alkyl,
(3) CycA or
(4) C1-8 alkyl substituted with 1 to 5 of groups selected from the following (a) to (f):
(a) CycA,
(b) guanidino,
(c) xe2x80x94NR77R78, wherein R77 and R78 have the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
(d) xe2x80x94OR77, wherein R77 has the same meaning as above,
(e) xe2x80x94COR76, wherein R76 has C1-4 alkyl, phenyl, xe2x80x94NR77R78, wherein all symbols have the same meanings as above, xe2x80x94OR77, wherein R77 has the same meaning as above, or C1-4 alkyl substituted with phenyl, and
(f) cyano;
R74 is
(1) hydrogen,
(2) C1-8 alkyl,
(3) CycA, or
(4) C1-8 alkyl substituted with 1 to 5 of groups selected from the following (a) to (h), wherein one carbon atom may be replaced by oxygen, sulfur atom or xe2x80x94NR84:
(a) CycA,
(b) guanidino,
(c) xe2x80x94SiR79R80R81, wherein R79, R80 and R81 are the same or different to represent C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl,
(d) xe2x80x94NR77R78, wherein all symbols have the same meanings as above,
(e) xe2x80x94OR77, wherein R77 has the same meaning as above,
(f) xe2x80x94COR76, wherein R76 has the same meaning as above,
(g) cyano,
(h) xe2x80x94P(O)(OR82)2, wherein all symbols have the same meaning as above;
CycA included in R, R1, R2, R4, R5, R7, R8, R10, R16, R71, R72, R73, R74 and R83 are the same or different and CycA, CycB, CycC, CycD, CycE and CycF, independently, may be substituted with 1 to 5 of R27;
R27 is
(1) C1-8 alkyl,
(2) halogen atom,
(3) xe2x80x94NR11R12,
(4) xe2x80x94OR13,
(5) a C5-10 mono-or bi-cyclic carboring,
(6) nitro,
(7) CF3,
(8) cyano,
(9) a 5-10 membered mono- or bi-cyclic heteroring
(10) xe2x80x94SR14,
(11) xe2x80x94COR15,
(12) oxo,
(13) xe2x80x94SO2R15,
(14) xe2x80x94OCF3 or
(15) C1-8 alkyl substituted with 1-5 of group selected from the following (a) to (m)
(a) halogen atom,
(b) xe2x80x94NR11R12,
(c) xe2x80x94OR13,
(d) a C5-10 mono- or bi-cyclic carboring,
(e) nitro,
(f) CF3,
(g) cyano,
(h) a 5-10 membered mono- or bi-cyclic heteroring,
(j) xe2x80x94SR14,
(k) xe2x80x94COR15,
(l) xe2x80x94SO2R15,
(m) xe2x80x94OCF3,
wherein
R11 and R12 are the same or different to represent hydrogen, C1-4 alkyl, xe2x80x94COOxe2x80x94(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,
R13 and R14 are the same or different to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
R15 is C1-4 alkyl, phenyl, xe2x80x94NR11R12, wherein all symbols have the same meanings as above, xe2x80x94OR13, wherein R13 is the same meaning as above, or C1-4 alkyl substituted with phenyl, or a non-toxic salt thereof,
(2) a method for the preparation thereof and
(3) a pharmaceutical agent comprising the benzene-fused heteroring derivative and non-toxic salt thereof as active ingredient.
In the compound of formula (I), in 
which AA1 and R together form, 
is a 5-12 membered heteroring containing 1-3 of nitrogen, 1 of oxygen, and/or 1 of sulfur (this heteroring may be substituted with 1-5 of R27).
And to describe 
concretely, it is 
wherein J1 is oxygen, sulfur, xe2x80x94NR29xe2x80x94, wherein R29 is hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA, C1-3 alkylene or C2-3 alkenylene,
J2 is a single bond or C1-2 alkylene,
Y2 is xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94 or C1-2 alkylene,
J3 is carbonyl or C1-3 alkylene,
Y3 is C1-3 alkylene, oxygen or xe2x80x94NR29xe2x80x94, wherein R29 is the same meaning as above,
R28 is hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA, or
R28 is taken together with R1to form C2-4 alkylene, and the other symbols have the same meaning as above and each ring may be substituted with 1-5 of R27.
In the compound of formula (I), in 
which AA2 represents, CycC is a 3-17 membered heteroring which contains 1-2 of nitrogen, 1 of oxygen and/or 1 of sulfur (this ring may be substituted with 1-5 of R27).
And to describe 
concretely, 
wherein J4, Y4 and L4 are the same or different to represent a single bond or C1-3 alkylene, wherein J4, Y4 and L4 do not represent a single bond at the same time,
J5 is C1-6 alkylene,
Y5 is a single bond, C1-3 alkylene or xe2x80x94NR67xe2x80x94, wherein R67 is hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,
J8 is C1-5 alkylene, wherein one carbon atom may be replaced by oxygen,
Y8 is a single bond or C1-4 alkylene,
L8 is xe2x80x94Nxe2x80x94 or xe2x80x94CHxe2x80x94,
and the other symbols have the same meaning as above and each ring may be substituted with 1-5 of R27.
And in 
which AA2 represents, CycD is a C3-14 mono- or bi-cyclic carboring or 3-14 membered heteroring which contains 1-2 of nitrogen, 1 of oxygen and/or 1 of sulfur (this carboring and heteroring may be substituted with 1-5 of R27).
And to describe 
concretely, it is 
wherein J6 and Y6 are the same or different to represent a single bond or C1-3 alkylene, wherein J6 and Y6 do not represent a single bond at the same time,
J7 is C1-6 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR67xe2x80x94, wherein R67 has the same meaning as above,
J9 is C1-3 alkylene, oxygen, sulfur or xe2x80x94NR67xe2x80x94, wherein R67 is the same meaning as above,
and the other symbols have the same meanings as above and each ring may be replaced by 1-5 of R27.
In the compounds of the formula (I), in 
which AA1 and AA2 together form,
CycE is a 4-18 membered heteroring which contains 1-2 of nitrogen, 1 of oxygen and/or 1 of xe2x80x94S(O)pxe2x80x94 (this heteroring may be substituted with 1-5 of R27).
And to describe 
concretely, it is 
wherein 
is a single bond or a double-bond,
J10 and Y10 are the same or different to represent a single bond or C1-3 alkylene,
L10 is a single bond, C1-3 alkylene, xe2x80x94NR57xe2x80x94, wherein R57 is hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl, xe2x80x94Nxe2x95x90, oxygen or xe2x80x94S(O)pxe2x80x94, wherein p is 0 or an integer of 1 to 2,
J12 and Y12 are the same or different to represent a single bond or C1-3 alkylene,
L12 is C1-3 alkylene, xe2x80x94NR57xe2x80x94, wherein R57 is the same meaning as above), xe2x80x94Nxe2x95x90, xe2x95x90Nxe2x80x94, oxygen or xe2x80x94S(O)pxe2x80x94, wherein p has the same meaning as above,
and the other symbols have the same meanings as above and each ring may be substituted with 1-5 of R27.
And in 
which AA1 and AA2 together form,
CycF is a 5-8 membered heteroring containing 2 of nitrogen.
And to describe 
concretely, it is 
wherein J11 is carbonyl or C2-4 alkylene and the other symbols have the same meaning as above and the ring therein may be substituted with 1-5 of R27.
In the present specification, C1-4 alkyl is methyl, ethyl, propyl, butyl and isomers thereof.
In the present specification, C1-8 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In the present specification, C2-8 alkenyl is, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl containing 1-3 of double bond and isomers thereof. For example, vinyl, propenyl, butenyl, hexenyl, hexadienyl, octadienyl, etc. are included.
In the present specification, C2-8 alkynyl is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl containing 1-3 of triple bond and isomers thereof. For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, etc. are included.
In the present specification, C1-4 alkyl substituted with phenyl is phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl and isomers thereof.
In the present specification, C1-8 alkyl substituted with phenyl is phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl and isomers thereof.
In the present specification, C1-2 alkylene is, methylene, ethylene and isomers thereof.
In the present specification, C1-3 alkylene is, methylene, ethylene, trimethylene and isomers thereof.
In the present specification, C1-4 alkylene is methylene, ethylene, trimethylene, tetramethylene and isomers thereof.
In the present specification, C1-5 alkylene is methylene, ethylene, trimethylene, tetramethylene, pentamethylene and isomers thereof
In the present specification, C1-6 alkylene is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
In the present specification, C2-4 alkylene is ethylene, trimethylene, tetramethylene and isomers thereof.
In the present specification, C2-6 alkylene is ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
In the present specification, C2-8 alkylene is ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof.
In the present specification, C2-6 alkylene whose one carbon atom may be replaced by oxygen, sulfur, xe2x80x94NR20xe2x80x94, xe2x80x94NR40xe2x80x94 or xe2x80x94NR60xe2x80x94 is ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof, wherein one carbon atom thereof may be replaced by oxygen, sulfur, xe2x80x94NR20xe2x80x94, xe2x80x94NR40xe2x80x94, or xe2x80x94NR60xe2x80x94, for example, such groups are xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94, etc.
In the present specification, C2-8 alkylene whose one carbon atom may be replaced by oxygen, sulfur, xe2x80x94NR20xe2x80x94, xe2x80x94NR40xe2x80x94 or xe2x80x94NR60xe2x80x94 is ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof, wherein one carbon atom may be replaced by oxygen, sulfur, xe2x80x94NR20xe2x80x94, xe2x80x94NR40xe2x80x94 or xe2x80x94NR60xe2x80x94, for example, such groups are xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3) xe2x80x94CH2xe2x80x94CH2xe2x80x94, etc.
In the present specification, C2-3 alkenylene means vinylene and allylene and isomers thereof.
In the present specification, C1-4 alkoxy is methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In the present specification, C3-6 alkylene is trimethylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
In the present specification, halogen atom means chlorine, fluorine, bromine and iodine atom.
In the present specification, mono- or bi-cyclic C5-10 carboring is mono- or bi-cyclic C5-10 carboaryl or partially or completely saturated one thereof. For example, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, adamantyl ring, etc. are included.
In the present specification, mono-, bi- or tri-cyclic C3-15 carboring is mono-, bi- or tri-cyclic carboaryl or partially or completely saturated one thereof. For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene, adamantyl ring etc. are included.
In the present specification, mono- or bi-cyclic 5-10 membered heteroring containing 1-4 of nitrogen, 1 of oxygen and/or sulfur is mono- or bi-cyclic 5-10 membered heteroaryl containing 1-4 of nitrogen, 1 of oxygen and/or sulfur or partially or completely saturated one thereof.
Above 5-10 membered mono- or bi-cyclic heteroaryl containing 1-4 of nitrogen, 1 of oxygen and/or 1 of sulfur is, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, oxepine, thiophene, thiaine (thiopyrane), thiepine, oxazole, isooxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, etc.
Above partially or completely saturated mono- or bi-cyclic 5-10 membered heteroaryl containing 1-4 of nitrogen, 1 of oxygen and/or 1 of sulfur is, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane), tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydrooxazole), oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole, oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole), thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole), dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, etc.
In the present specification, a 3-15 membered mono-, bi- or tri-cyclic heteroring containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur is 3-15 membered mono-, bi- or tri-cyclic heteroaryl containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur or partially or completely saturated one thereof.
Above 3-15 membered mono-, bi- or tri-cyclic heteroring containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur is, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, oxepine, oxazepine, thiophene, thiaine (thiopyrane), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzoxadiazole, benzothiazole, benzoimidazole, carbazole, acridine ring, etc. Above partially or completely saturated mono-, bi- or tri-cyclic 3-15 membered heteroring containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur is, aziridine, oxirane, azetidine, oxetane, thiirane, thietane, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane), tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydroxazole), oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole, oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole), thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole), dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, indoloxazepine, indolotetrahydroxazepine, indoloxadiazepine, indolotetrahydroxadiazepine, indolothiazepine, indolotetrahydrothiazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indolazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, benzofurazane, benzothiadiazole, benzotriazole, camphor, imidazothiazole, dihydrocarbazole, tetrahydrocarbazolei, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane, dioxane, dioxazine ring etc.
In the present specification, C5-8 carboring is C5-8 mono-cyclic carboaryl or partially or completely saturated one thereof. For example, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, cycloheptatriene, cyclooctatriene, etc. are included.
In the present specification, 5-8 membered heteroring containing 1 or 2 of nitrogen, 1 of oxygen and/or 1 of sulfur is, mono-cyclic 5-8 membered heteroaryl containing 1 or 2 of nitrogen, 1 of oxygen and/or 1 of sulfur, or partially or completely saturated one thereof. For example, pyridine, piperidine, pyrrole, pyrrolidine, azepine, hexahydroazepine, diazepine, furan, dioxane, dioxole, pyran, oxepine, oxocine, thiophene, thiane, thiepine, oxathiolane, oxazolidine, pyrazole, oxazole, pyrazine, pyrimidine, pyridazine, etc. are included.
In the present specification, a 5-12 membered heteroring containing 1-3 of nitrogen, 1 of oxygen and/or 1 of sulfur atom, i.e. 
is, for example, a ring represented by 
Specifically, 2-oxo-1,3,4-triazoline, 5-oxo-1,2,4-oxadiazoline, 5-oxo-1,2,4-thiadiazoline, 4-oxoimidazoline, 3,4-dihydro-4-oxopyrimidine, 3,4,5,6-tetrahydro-4-oxopyrimidine, 2-oxoindoline, 2-oxo-tetrahydroquinoline, 1,2-dihydro-2-oxoquinazoline, 1,2-dihydro-2-oxoquinoxaline, 3-oxopyrazolidine, perhydro-3-oxopyridazine, 2-oxo-1,3,4-oxadiazolidine, perhydro-2-oxo-1,3,4-oxadiazine, etc. are included.
In the specification, 3-17 membered heteroring containing 1-2 of nitrogen, 1 of oxygen and/or 1 of sulfur represented by CycC is, for example, a ring represented by 
Specifically, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, thiazolidine, indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, etc. are included.
In the specification, a C3-14 mono- or bi-cyclic carboring or 3-14 membered heteroring containing 1-2 of nitrogen, 1 of oxygen, and/or 1 of sulfur represented by CycD is, for example, a ring represented by 
Specifically, cyclopentane, cyclohexane, cycloheptane, benzene, indan, tetrahydronaphthalene, oxorane, oxane, thiorane, thian, pyrrolidine, piperidine, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, 7-azabicyclo[2.2.1]heptane, 7-oxobicyclo[2.2.1]heptane, 7-thiabicyclo[2.2.1]heptane, etc. are included.
In the specification, 4-18 membered heteroring containing 1-2 of nitrogen, 1 of oxygen and/or 1 of xe2x80x94S(O)pxe2x80x94, i.e. CycE is, for example, a ring represented by 
Specifically, 2-oxopyrrolidine, 2-oxopiperidine, 2-oxoperhydroazepine, 2-oxopiperazine, 3-oxomorpholine, 1,1,-dioxo-3-isothiazolidine, 1,1-dioxo-3-isothiazine, 4-oxodiazepine, 2-oxoindoline, 2-oxo-tetrahydroquinoline, 1,1-dioxo-3-benzisothiazolidine, 1,1-dioxo-3-benzisothiazine, etc. are included.
In the present invention, 5-8 membered heteroring which contains 2 of nitrogen. i.e. CycF is, for example, a ring represented by 
Specifically, 2,4-dioxoimidazolidine, 2-oxopiperazine, 2-oxoperhydrodiazepine substituted by R1 and R2 are included.
In the present invention, as may be easily understood by those skilled in the art, the symbol: 
indicates that the substituent attached thereto is in front of the sheet (xcex2-position) unless specified, 
indicates that the substituent attached thereto is behind the sheet (xcex1-position) unless specified, and 
indicates that the substituent attached thereto is in xcex2-position or xcex1-position or a mixture thereof.
In the formula (I), all groups represented by R are preferable, but preferably, R is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) CycA,
(iv) C1-8 alkyl substituted with a group selected from CycA and nitro, 
more preferably, C1-8 alkyl or C1-8 alkyl substituted with CycA or nitro, or 
Any group represented by R16 is preferable, but more preferably, R16 is
[I] (1) C1-8 alkyl,
(2) C2-8 alkenyl,
(3) C2-8 alkynyl,
(4) CycA, or
(5) C1-8 alkyl substituted with a group selected from CycA or xe2x80x94NHC(O)-CycA,
(6) C2-8 alkenyl substituted with CycA or
(7) C2-8 alkynyl substituted with CycA,
wherein CycA may be substituted with 1-5 of R27a, and
R27a, is (1) C1-8 alkyl,
(2) halogen,
(3) xe2x80x94NR11R12,
(4) xe2x80x94OR13,
(5) phenyl,
(6) nitro,
(7) CF3,
(8) cyano,
(9) tetrazole,
(10) xe2x80x94SR14,
(11) xe2x80x94COR15,
(12) oxo or
(13) C1-8 alkyl substituted with 1-5 of group selected from the following (a) to (k):
(a) halogen, (b) xe2x80x94NR11R12, (c) xe2x80x94OR13, (d) phenyl, (e) nitro, (f) CF3, (g) cyano, (h) tetrazole, (j) xe2x80x94SR14, (k) xe2x80x94COR15, or
[II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with a group selected from halogen, CF3, nitro, cyano or NR18R19 or
(b) (1) CycA containing 1-5 of substituent R27 or
(2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with CycA, which contains 1-5 of substituent R27,
wherein at least one of R27 described in (1) and (2) is selected from
(i) a C5-10 mono- or bi-cyclic carboring,
(ii) a 5-10 membered mono- or bi-cyclic heteroring,
(iii) xe2x80x94SO2R15, (iv) xe2x80x94OCF3 or
(v) C1-8 alkyl substituted with 1-5 of the group selected from (a) halogen, (b) xe2x80x94NR11R12, (c) xe2x80x94OR13, (d) a C5-10 mono-or bi-cyclic carboring, (e) nitro, (f) CF3, (g) cyano, (h) a 5-10 membered mono- or bi-cyclic heteroring, (j) xe2x80x94SR14, (k) xe2x80x94COR15, (1) xe2x80x94SO2R15 and (m) xe2x80x94OCF3 (at least one is a C5-10 mono-or bi-cyclic carboring, a 5-10 mono- or bi-cyclic heteroring, xe2x80x94SO2R15 or xe2x80x94OCF3))
Particularly preferably,
[I] (1) C1-8 alkyl,
(2) C2-8 alkenyl,
(3) C2-8 alkynyl,
(4) CycA or
(5) C1-8 alkyl substituted with a group selected from CycA or xe2x80x94NHC(O)-CycA,
(6) C2-8 alkenyl substituted with CycA or
(7) C2-8 alkynyl substituted with CycA,
wherein CycA is a mono- or bi-cyclic C5-10 carboaryl which may be substituted with 1-5 of R27 or partially or completely saturated one thereof, or mono- or bi-cyclic 5-10 membered heteroaryl containing 1-2 of nitrogen, 1-2 of oxygen and/or 1 of sulfur atom, or partially or completely saturated one thereof or
[II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with a group selected from halogen atom, CF3, nitro, cyano and NR18R19, or
(b) CycA containing 1-5 of substituent R27 or
(2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with CycA, which contains 1-5 of substituent R27,
wherein at least one of R27 described in (1) and (2) is selected from
(i) a C5-10 mono- or bi-cyclic carboring,
(ii) a 5-10 membered mono- or bi-cyclic heteroring,
(iii) xe2x80x94SO2R15, (iv) xe2x80x94OCF3 or
(v) C1-8 alkyl substituted with 1-5 of group selected from (a) halogen, (b) xe2x80x94NR11R12, (c) xe2x80x94OR13, (d) a C5-10 mono- or bi-cyclic carboring, (e) nitro, (f) CF3, (g) cyano, (h) a 5-10 membered mono- or bi-cyclic heteroring, (j) xe2x80x94SR14, (k) xe2x80x94COR15, (1) xe2x80x94SO2R15 and (m) OCF3, wherein at least one group is selected from a C5-10 mono- or bi-cyclic carboring or a 5-10 membered mono- or bi-cyclic heteroring, xe2x80x94SO2R15 or OCF3,
above CycA is C5-10 mono- or bi-cyclic carboaryl or partially or completely saturated one, or 5-10 membered mono- or bi-cyclic heteroaryl containing 1-2 of nitrogen, 1-2 of oxygen and/or 1 of sulfur, or partially or completely saturated one thereof.
Particularly preferably, [I] (1) C1-4 alkyl, (2) C2-4 alkenyl, (3) C2-4 alkynyl, (4) CycA or (5) C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl substituted with CycA which is preferably cyclopentane, cyclohexane, benzene, naphthalene, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, indole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, benzothiophene, benzofuran, benzoxazole, tetrahydroquinoline, tetrahydroquinazoline, tetrahydroquinoxaline, optionally substituted with 1-5 of R27a or
[II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with a group selected from halogen, CF3, nitro, cyano or NR18R19 or
(b) (1) CycA which contains 1-5 of substituent R27, or
(2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with CycA which contains 1-5 of substituent R27,
wherein at least one of R27 described in (1) and (2) is selected from
(i) a C5-10 mono- or bi-cyclic carboring,
(ii) a 5-10 membered mono- or bi-cyclic heteroring,
(iii) xe2x80x94SO2R5, (iv) xe2x80x94OCF3, or
(v) C1-8 alkyl substituted with 1-5 of group selected from (a) halogen atom, (b) xe2x80x94NR11R12, (c) xe2x80x94OR13, (d) a C5-10mono- or bi-cyclic carboring, (e) nitro, (f) CF3, (g) cyano, (h) a 5-10 membered mono- or bi-cyclic heteroring, (j) xe2x80x94SR14, (k) xe2x80x94COR15, (1) xe2x80x94SO2R15 or (m) xe2x80x94OCF3, wherein at least one group is selected from a C5-10 mono- or bi-cyclic carboring, a 5-10 membered mono- or bi-cyclic heteroring, xe2x80x94SO2R15 or xe2x80x94OCF3, and
CycA is preferably cyclopentane, cyclohexane, benzene, naphthalene, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, indole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, benzothiophene, benzofuran, benzoxadiazole, tetrahydroquinoline, tetrahydroquinazoline, or tetrahydroquinoxaline.
In the formula (I), AA1 is preferably a single bond, 
which is formed with R, but more preferably, AA1 is a single bond or 
Any group represented by R1 is preferable, but more preferably, R1 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with NH2, C1-4 alkoxy, SH, SCH3, phenyl, hydroxyphenyl, COOH, CONH2, guanidino, imidazole or indole. Particularly preferably, R1 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with C1-4 alkoxy or phenyl. Then, any group represented by R2 is preferable, but hydrogen is particularly preferable.
And C3-6 alkylene which R1 and R2 together form is also preferable.
Any group represented by R3 is preferable, but more preferably R3 is hydrogen or C1-4 alkyl.
And C2-4 alkylene which R3 and R1 together form is also preferable.
In the formula (I), any group represented by AA2 is all preferable, but more preferably, AA2 is a single bond, 
Particularly preferably, AA2 is a single bond, 
Any group represented by R4 is preferable, but more preferably, R4 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with NH2, C1-4 alkoxy, SH, SCH3, phenyl, hydroxyphenyl, COOH, CONH2, guanidino, imidazole or indole. Particularly preferably, R4 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with C1-4 alkoxy or phenyl. Then, any group represented by R5 is preferable, and hydrogen is particularly preferable.
And C3-6 alkylene which R4 and R5 together form is also preferable.
Any group represented by R6 is preferable, but more preferably R6 is hydrogen or C1-4 alkyl.
And C2-4 alkylene which R6 and R4 together form is also preferable.
Any group represented by R48 is preferable, but more preferably, R48 is
[I] hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl, or
[II] C2-6 alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or xe2x80x94NR47xe2x80x94, wherein R47 is hydrogen or C1-4 alkyl to be formed together with R4, when AA1 is a single bond. Particularly preferably, R48 is [I] hydrogen atom or C1-4 alkyl, or
[II] when AA1 is a single bond, taken together with R to form tetramethylene, pentamethylene, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94.
In the formula (I), any group which AA1 and AA2 together form is preferable, but preferably, it is 
particularly preferably, it is 
Any group represented by R7 is preferable. More preferably, R7 is hydrogen atom, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with NH2, C1-4 alkoxy, SH, SCH3, phenyl, hydroxyphenyl, COOH, CONH2, guanidino, imidazole or indole.
Particularly preferably, R7 is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with C1-4 alkoxy or phenyl. Then, any group represented by R8 is preferable, but hydrogen is most preferable.
And C3-6 alkylene which R7 and R8 together form is also preferable.
Any group represented by R9 is preferable, but more preferably R9 is hydrogen or C1-4 alkyl.
And C2-4 alkylene which R9 and R7 together form is also preferable.
Any group represented by R10 is preferable, but more preferably R10 is C1-6 alkyl, C2-4 alkenyl, CycA or C1-6 alkyl or C2-4 alkenyl substituted with COR71, NR72R73, hydroxy, OR74 or CycA, particularly preferably C1-4 alkyl, or C1-4 alkyl substituted with phenyl, NR72R73 or C3-6 cycloalkyl.
Any group represented by R10 is preferable, but more preferably R10 is C1-6 alkyl, CycA or C1-6 alkyl substituted with COR71, NR72R73, hydroxy, OR74 or CycA, more preferably C1-4 alkyl, C2-4 alkenyl, or C1-4 alkyl or C2-4 alkenyl substituted with phenyl, NR72R73, C3-6 cycloalkyl, piperidine or pyrrolidine. 
is preferably, 
and more preferably, 
In the ring represented by 
the C5-8 carbocycle which is a condensed ring of the rings represented by 
or 5-8 membered heteroring which contains 1 or 2 of nitrogen, 1 of oxygen and/or 1 of sulfur atom, are all preferable, but more preferably, C5-6 carboring or 5-6 membered heteroring containing 1 or 2 of nitrogen, 1 of oxygen and/or 1 of sulfur atom, concretely, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pyridine, piperidine, pyrrole, pyrrolidine, furan, dioxane, dioxole, pyran, thiophene, thian, thiepine, oxathiolane, oxazolidine, pyrazole, oxazole, pyrazine, pyrimidine, pyridazine.
R83 is preferably hydrogen atom, C1-4 alkyl, or C1-4 alkyl substituted with Cyc, cyano, xe2x80x94OR69 or xe2x80x94COR68, and more preferably C1-4 alkyl or C1-4 alkyl substituted with Cyc.
R10 is preferably xe2x80x94OR74, more preferably hydroxy, C1-4 alkoxy, or C1-4 alkoxy substituted with phenyl.
In the compounds of formula (I), the following compounds are preferred;
the compound of (I-1A) 
wherein all symbols have the same meanings as above, the compound of formula (I-2A) 
wherein all symbols have the same meanings as above, the compound of formula (I-3A) 
wherein all symbols have the same meanings as above, the compound of formula (I-4A) 
wherein all symbols have the same meanings as above, the compound of formula (I-5A) 
wherein all symbols have the same meanings as above, the compound of formula (I-6A) 
wherein all symbols have the same meanings as above, the compound of formula (I-7A) 
wherein all symbols have the same meanings as above, the compound of formula (I-8A) 
wherein all symbols have the same meanings as above, the compound of formula (I-9A) 
wherein all symbols have the same meanings as above, the compound of formula (I-10A) 
wherein all symbols have the same meanings as above, the compound of formula (I-1B) 
wherein all symbols have the same meanings as above, the compound of formula (I-2B) 
wherein all symbols have the same meanings as above, the of formula (I-3B) 
wherein all symbols have the same meanings as above, the compound of formula (I-1C) 
wherein all symbols have the same meanings as above, the compound of formula (I-2C) 
wherein all symbols have the same meanings as above, the compound of formula (I-3C) 
wherein all symbols have the same meanings as above, the compound of formula (I-4C) 
wherein all symbols have the same meanings as above, the compound of formula (I-5C) 
wherein all symbols have the same meanings as above, the compound of formula (I-6C) 
wherein all symbols have the same meanings as above, the compound of formula (I-7C) 
wherein all symbols have the same meanings as above, the compound of formula (I-8C) 
wherein all symbols have the same meanings as above, the compound of formula (I-9C) 
wherein all symbols have the same meanings as above, the compound of formula (I-10C) 
wherein all symbols have the same meanings as above, the compound of formula (I-1D) 
wherein all symbols have the same meanings as above, and the compound of formula (I-2D) 
wherein all symbols have the same meanings as above.
Particularly, the compounds described in the following tables 1 to 30 and the compounds described in the examples or non-toxic salts thereof are preferable. In the following tables, all symbols have the same meanings as above.
The Methods for the Preparation of the Compound of the Present Invention
(1) Among the compounds of formula (I), the compound wherein AA1 and AA2 represent a single bond at the same time, none of R, R7, R8, R10or 
contains carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, and R does not represent hydrogen, i.e. the compound of formula (IA) 
wherein RA, R7A, R8A and R10A and 
have the same meanings as R, R7, R8, R10 and 
respectively, with proviso that none of them contains carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono and RA does not represent hydrogen, may be prepared by subjecting to a reaction a compound of formula (IIA) 
wherein X is halogen atom or a leaving group such as mesyl and tosyl and the other symbols have the same meanings as above, and a compound of formula (IIB) 
wherein all symbols have the same meanings as above. The reaction of the compound of formula (IIA) and the compound of formula (IIB) is, for example, carried out in an organic solvent (dimethylformamide, acetonitrile, etc.) in the presence or absence of a tertiary amine (triethylamine, N-methylmorpholine, diisopropylethylamine, etc.), a base (sodium hydride etc.), an alkali (potassium carbonate, sodium carbonate, etc.) or fluoride (sodium fluoride, potassium fluoride, cesium fluoride, etc.) at a temperature of 20 to 40xc2x0 C.
[2] Among the compounds of formula (I), wherein AA1 and AA2 are a single bond at the same time, R is hydrogen and none of R7, R8, R10 and 
contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphono, i.e. the compound of formula (IB) 
wherein all symbols have the same meanings as above, may be prepared by subjecting to a deprotection reaction the compound, among the compounds of formula (IA), wherein RA is a protective group of amino, i.e. the compound of formula (IA-1) 
wherein RA-1 is a protective group of amino and the other symbols have the same meanings as above.
As protective groups for amino group, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl, 9-fluorenylmethoxycarbonyl may be included, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
Deprotection reaction for protective groups of amino group is known, for example,
1) deprotection reaction under alkaline conditions,
2) deprotection reaction under acidic conditions,
3) deprotection reaction by hydration, etc. may be included.
To explain these methods concretely,
1) deprotection reaction under alkaline conditions is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, dimethylformamide, etc.) using a hydroxide of alkali metals (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metals (barium hydroxide, calcium hydroxide, etc.), organic amine (triethylamine, N-methylmorpholine, diisopropylethylamine, piperidine, etc.) or a quaternary ammonium salt (tetrabutyl ammonium fluoride etc.) or a solution thereof or a mixture thereof at a temperature of 0 to 40xc2x0 C.;
2) deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.), using organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.) or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrobromic acid/acetic acid, etc.) at a temperature of 0 to 100xc2x0 C.;
3) deprotection reaction by hydration is, for example, carried out in a solvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles such as acetonitrile, amides such as dimethylformamide, water, ethyl acetate, acetic acid or a mixture of more than two from above, etc.) in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.) under the atmosphere of hydrogen of normal or suppressed pressure, or in the presence of ammonium formate at a temperature of 0 to 200xc2x0 C.
As easily understood by those skilled in the art, the compounds of the present invention may be easily prepared by selecting these reactions.
[3] Among the compounds of formula (I), wherein AA1 and AA2 are a single bond at the same time, and at least one of R, R7, R8, R10 or 
contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphono or R is hydrogen, i.e. the compound of formula (IC) 
wherein RC, R7C, R8C, R10C and 
have the same meanings as R, R7, R8, R10 and 
respectively, with proviso that at least one contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphono or R is hydrogen, may be prepared by subjecting to deprotection reaction of protective groups of carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, the compound among the compounds of formula (IA) prepared by a previous method, wherein at least one of RA, R7A, R8A, R10A or 
contains a protected form of carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, i.e. the compound of formula (IA-2) 
wherein RA-2, R7A-2, R8A-2, R10A-2
have the same meanings as RA, R7A, R8A, R10A and 
respectively, with proviso that at least one of RA-2, R7A-2, R8A-2, R10A-2 and 
is a protected form of carboxy, hydroxy, amidno, thiol, guanidino, amidino or phosphono, or RA-2 is a protective group of amino, and the other symbols have the same meanings as above, or the compound among the compounds of formula (IB) prepared by a method above described, wherein at least one group is a protected form of carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, i.e. the compound of formula (IB-1) 
wherein all symbols have the same meanings as above.
Protective groups for carboxy include, for example, methyl, ethyl, t-butyl and benzyl.
Protective groups for hydroxy include, for example, methoxymethyl, 2-tetrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl and benzyl.
Protective groups for amino include the ones shown above.
Protective groups for thiol include, for example, benzyl, methoxybenzyl, methoxymethyl, 2-tetrahydropyranyl, diphenylmethyl and acetyl.
Protective groups for guanidino and amidino include, for example, benzyloxycarbonyl, t-butoxycarbonyl and 9-fluorenylmethoxycarbonyl.
Protective groups for phosphono include, for example, C1-2 alkyl, phenyl, benzyl, 2,2,2-trichloroethyl and cyanoethyl.
As to protective groups for carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono group, other groups than above listed may also be used instead, if easily and selectively eliminated. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
Deprotection reactions of the protective groups of carboxy, hydroxy, amino, thiol, guanidino or amidino are well known, for example,
1) a deprotection reaction under alkaline conditions,
2) a deprotection reaction under acidic conditions,
3) a deprotection reaction by hydration,
4) a deprotection reaction of silyl-containing groups, etc. may be included.
The methods of 1), 2) and 3) are carried out by the methods described above.
4) A deprotection reaction of silyl-containing group is carried out, for example, in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride at a temperature of 0 to 40xc2x0 C.
Deprotection reaction of protective groups of phosphono is known, for example,
(a) Elimination of C1-2 alkyl is carried out in an organic solvent such as chloroform using halogenated trimethylsilyl (chlorotrimethylsilyl, bromotrimethylsilyl, iodotrimethylsilyl, etc.) as a reagent, in the presence or absence of alkali metal iodide (sodium iodide, potassium iodide, etc.) at a temperature of 0 to 40xc2x0 C.
(b) Elimination of phenyl is carried out under atmosphere of hydrogen in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.) or without a solvent in the presence or absence of a catalyst such as platinum oxide and an organic acid such as acetic acid or an inorganic acid such as hydrochloric acid at a temperature of 0 to 50xc2x0 C. for 24 hours to 3 days.
(c) Elimination of benzyl is carried out under atmosphere of hydrogen in an organic solvent (methanol, ethanol, tetrahydrofuran, pyridine, acetic acid, etc.) in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, etc.) at a temperature of 0 to 50xc2x0 C.
(d) Elimination of 2,2,2-trichloroethyl is carried out in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.) or without a solvent using a micropowder of zinc and others and an organic acid such as acetic acid or an inorganic acid such as hydrochloric acid at a temperature of 0 to 50xc2x0 C.
(e) Elimination of cyanoethyl is carried out in a solvent (water, methanol, ethanol, tetrahydrofuran, pyridine, etc.) or without a solvent, in the presence of a base (triethylamine, dimethylamine, t-butylamine, etc.) at a temperature of 0 to 100xc2x0 C.
As easily understood by those skilled in the art, the target compounds of the present invention may be easily prepared by selecting these reactions.
[4] Among the compounds of formula (I), wherein AA1 and AA2 do not represent a single bond at the same time, and none of R, AA1, AA2, R7 R8, R10 and 
xe2x80x83contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphono, i.e. the compound of formula (ID) 
xe2x80x83wherein AA1A and AA2A have the same meanings as AA1 and AA2, with proviso that no group contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphono, and AA1A and AA2A do not represent a single bond at the same time, and the other symbols have the same meanings as above, may be prepared according to the following method of (A) or (B).
(A) The compound of formula (ID) may be prepared by subjecting to amidation reaction the compound of formula (IIC)
RA-AA1A-AA2Axe2x80x94OHxe2x80x83xe2x80x83(IIC), 
wherein all symbols have the same meanings as above, and the compound of formula (IB) above described.
Amidation reaction is known, for example,
1) a method using acid halide,
2) a method using mixed anhydride,
3) a method using a condensing agent (EDC, DCC, etc.), etc.
To explain these methods concretely,
1) the method using acid halide is carried out, for example, by subjecting to a reaction carboxylic acid and acid-halogenating agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent, at a temperature between xe2x88x9220xc2x0 C. and refluxing temperature, and then subjecting to a reaction thus obtained acid halide in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at a temperature between 0 to 40xc2x0 C.
And it may be carried out by subjecting to a reaction with acid halide in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (an aqueous solution of sodium bicarbonate or sodium hydroxide, etc.) at a temperature between 0 to 40xc2x0 C.
2) The method using mixed anhydride is carried out, for example, by subjecting to a reaction in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), carboxylic acid with acid halide (pivaloyl chloride, tosyl chloride, mesylchloride, etc.) or acid derivative (chloroethyl formate, chloroisobutyl formate, etc.) at a temperature between 0 to 40xc2x0 C., and then subjecting to a reaction thus obtained mixed anhydride with amine in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at a temperature between 0 to 40xc2x0 C.
3) The method using a condensing agent is carried out, for example, in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or without a solvent, in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), using a condensing agent (1,3-dicychlorohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1xe2x80x2-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, etc.) in the presence or absence of 1-hydroxybenzotriazole (1-HOBt), by subjecting to a reaction carboxylic acid and amine at a temperature between 0 and 40xc2x0 C.
The reactions 1), 2) and 3) are desirably carried out under atmosphere of inert gas (argon, nitrogen, etc.) and anhydrous conditions.
(B) The compound of formula (ID) may be prepared by subjecting to a reaction the compound of formula (IID) 
xe2x80x83wherein all symbols have the same meanings as above, and the compound of formula (IIB) above described. The reaction of the compound of formula (IID) and the compound of formula (IIB) is carried out according to the same method of the reaction of the compound of formula (IIA) and the compound of formula (IIB) above described.
[5] Among the compounds of formula (I), wherein AA1 and AA2 do not represent a single bond at the same time, and at least one of R, AA1, AA2, R7, R8, R10 and 
represents a group which contains carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, i.e. the compound of formula (IE) 
wherein RE, AA1E, AA2E, R7E, R8E, R10E and 
have the same meanings as R, AA1, AA2, R7, R8, R10 and 
respectively, with proviso that at least one of them contains carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, or RE is hydrogen, and the other symbols have the same meanings as above, may be prepared by subjecting to a deprotection reaction of protective group of carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, the compound among the compounds of formula (ID), which contains at least one protected form of carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, i.e. the compound of formula (ID-1) 
wherein RA-3, AA1A-3, AA2A-3, R7A-3, R8A-3, R10A-3 and 
have the same meanings as RA, AA1A, AA2A, R7A, R8A, R10A and 
respectively, with proviso that at least one of RA-3, AA1A-3, AA2A-3, R7A-3, R8A-3, R10-3 and 
contains at least one protected form of carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono or RA-3 is a protected form of amino, and the other symbols have the same meanings as above.
Deprotection reaction of the protective groups of carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono is carried out according to the method described above.
The compound of formula (IA) above described may also be prepared by subjecting the compound of formula (IB) to a reaction of (A) amidation, (B) sulfonamideation, (C) forming an urea, (D) forming an urethane, (E) N-alkylation.
(A) Amidation Reaction is Carried out by Subjecting to a Reaction the Compound of Formula (IB) and the Compound of Formula (IIE-A) 
wherein R16A has the same meaning as R16, but R16A represents a group which does not contain carboxy, hydroxy, amino, thiol, guanidino or amidino. Amidation reaction is carried out according to the method described above.
(B) Sulfonamidation Reaction is Carried out by Subjecting to a Reaction the Compound of Formula (IB) and the Compound of Formula (IIE-B) 
wherein XB is halogen and the other symbols are the same meanings as above.
Sulfonamidation reaction is known, for example, it is carried out by subjecting sulfonic acid to a reaction with acid halide (oxalyl chloride, thionyl chloride, etc.) at a temperature of xe2x88x9220xc2x0 C. to refluxing temperature in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent, followed by subjecting thus obtained sulfonyl halide to a reaction with amine in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at a temperature of 0 to 40xc2x0 C.
(C) A Reaction to Form Urea is Carried out According to the Following Method of (1) or (2).
(1) A Method of Subjecting to a Reaction the Compound of Formula (IB) and the compound of formula (IIE-C-1)
R16Axe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(IIE-C-1) 
The reaction is carried out, for example, in an organic solvent (tetrahydrofuran, methylene chloride, diethyl ether, etc.) at a temperature of 0 to 100xc2x0 C.
(2) A Method of Subjecting to a Reaction the Compound of Formula (IB) and the Compound of Formula (IIE-C-2) 
xe2x80x83in the presence of phosgene or 1,1-carbonyldiimidazole
This reaction is carried out, for example, in an organic solvent (tetrahydrofuran, methylene chloride, diethyl ether, dimethylformamide, etc.) at a temperature of 0 to 120xc2x0 C.
(D) A Reaction to Form Urethane is Carried out According to the Following Method of (1) or (2).
(1) A Method of Subjecting to a Reaction the Compound of Formula (IB) and the Compound of Formula (IIE-D-1) 
wherein all symbols have the same meanings as above.
This reaction is carried out, for example, in an organic solvent (tetrahydrofuran, methylene chloride, diethyl ether, etc.) at a temperature of xe2x88x9278 to 40xc2x0 C.
(2) A Method of Subjecting to a Reaction the Compound of Formula (IB) and the Compound of Formula (IIE-D-2)
R16Axe2x80x94OHxe2x80x83xe2x80x83(IIE-D-2) 
in the presence of N,Nxe2x80x2-disuccinylcarbonate (DSC)
This reaction is carried out, for example, in an organic solvent (tetrahydrofuran, methylene chloride, diethyl ether, dimethylformamide, etc.) at a temperature of xe2x88x9278 to 120xc2x0 C.
(E) N-Alkylation Reaction is Carried out by Subjecting to a Reaction the Compound of Formula (IB) and the Compound of (IIE-E)
RXxe2x80x94XBxe2x80x83xe2x80x83(IIE-E), 
wherein RX is C1-8 alkyl, Cyc, C1-8 alkyl substituted with Cyc or nitro, or 
N-alkylation is known, for example, it is carried out in an inert organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc.) in the presence or absence of a base (triethylamine, pyridine, etc.) at a temperature of 0 to 100xc2x0 C.
Furthermore, the compound of formula (ID) may also be prepared according to the method of 1) or 2).
1) The compound of formula (ID) may be prepared by subjecting to amidation reaction the compound among the compounds of formula (IE), wherein RE is hydrogen atom, AA1A is a single bond, and none of AA2E, R7E, R8E, 
xe2x80x83or R10E contains carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, i.e. the compound of formula (IE-1) 
xe2x80x83and the compound of formula (IIF)
RA-AA1A-OHxe2x80x83xe2x80x83(IIF), 
xe2x80x83wherein all symbols have the same meanings as above.
2) The compound of formula (ID) may also be prepared by the reactions of the compound among the compounds of formula (IE), wherein RE is hydrogen, and none of AA1E, AA2E, R7E, R8E, 
xe2x80x83and R10E contains carboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, i.e. the compound of formula (IE-2) 
xe2x80x83wherein all symbols have the same meanings as above, and the compound of formula (IIE-A), (IIE-B), (IIE-C-1), (IIE-C-2), (IIE-D-1), (IIE-D-2) or (IIE-E).
That is, the compound of formula (ID) may also be prepared by subjecting to
2-A) an amidation reaction the compound of formula (IE-2) and the compound of formula (IIE-A),
2-B) a sulfonamidation reaction the compound of formula (IE-2) and the compound of formula (IIE-B),
2-C) a reaction to form urea the compound of formula (IE-2) and the compound of formula (IIE-C-1) or (IIE-C-2),
2-D) a reaction to form urethane the compound of formula (IE-2) and the compound of formula (IIE-D-1) or (IIE-D-2), or
2-E) an N-alkylation reaction the compound of formula (IE-2) and the compound of formula (IIE-E).
Amidation, sulfonamidation, reactions to form urea and urethane, and N-alkylation may be carried out according to the methods described above.
The compounds of formula (IIA), (IIB), (IIC), (IID), (IIE-A), (IIE-B), (IIE-C), (IIE-D), (IIE-E) and (IIF) are known per se or may be prepared according to known methods.
For example, among the compound of formula (IIB), the compound of formula (IIB-1) 
is known as CAS No. 4424-20-8 and the compound of formula (IIB-2) 
may be prepared according to the following reaction scheme (1). 
The compounds of formula (IIA) and (IID) may be prepared according to known methods, for example, the methods described in J. Med. Chem., 37, 563 (1994), EP 0623592-A, etc.
In each reaction of the present specification, reaction products may be purified by conventional techniques. For example, purification may be carried out by distillation under atmospheric or reduced pressure, by high performance liquid chromatography using silica gel or magnesium silicate, by washing or by recrystallization, etc. Purification may be carried out after each reaction, or after a series of reactions. Other starting materials and agents used in the present invention are known per se or may be prepared by conventional methods.
Pharmacological Activity of the Compounds of the Present Invention
The compound of formula (I) of the present invention has an inhibitory activity against cysteine proteases, and therefore it is useful as an agent for the prophylaxis and/or treatment of inflammatory diseases (periodontitis, arthritis, inflammatory bowel diseases, infectious diseases, pancreatitis, hepatitis, glomerulonephritis, endocarditis, myocarditis, etc.), diseases induced by apoptosis (graft versus host diseases, rejection of an organ transplantation, acquired immune deficiency syndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia, hairy cells leukemia, spondylopathy, disorders of respiratory apparatus, arthritis, HIV or HTLV-1 related diseases such as uveitis, virus-related diseases such as hepatitis C, cancer, collagenosis (systemic lupus erythematosus, rheumatoid arthritis, etc.), ulcerative colitis, Sjoegren""s syndrome, primary biliary cirrhosis, spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, autoimmune diseases such as insulin dependent (type I) diabetes, diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome, periodic thrombocytopenia, aplastic anemia, spontaneous thrombocytopenia, disseminated intravascular coagulation (DIC), etc.), hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) or hepatitis medicamentosa and cirrhosis, dementia such as Alzheimer""s diseases and Alzheimer""s senile dementia, cerebrovascular injury, nerve degeneration diseases, adult acute respiratory distress syndrome, infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma, arteriosclerosis, all kinds of lusus naturae, nephropathy, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy, etc.), diseases induced by disorders of immune response (graft versus host diseases, rejection of an organ transplantation, allergic diseases (bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis, diseases induced by house dusts, irritable pneumonia, food allergy, etc.), psoriasis, rheumatoid arthritis, etc.), auto immune diseases (insulin-dependent (type I) diabetes, systemic lupus erythematosus, Hashimoto""s diseases, multiple sclerosis, etc.), desease by decomposing various proteins which compose the organism (myodystrophy, cataract, periodontitis, hepatocyte desease by bile acid such as cholestatic cirrhosis, etc.), decomposition of alveolus elastica such as pulmonary emphysema, ischemic diseases (brain ischemia, brain disorders by ischemic reperfusion, myocardial infarction, ischemic hepatopathy, etc.), shock (septic shock, systemic inflammation response syndrome, endotoxin shock, acidosis, etc.), circulatory system disorders (arteriosclerosis, restenosis after percutaneous transluminal coronary angioplasty (PTCA), etc.)), blood coagulation disorders (thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignant tumor, acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC), parasitic diseases such as malaria, nerve degenerative diseases (Alzheimer-type dementia, Huntington""s chorea, Parkinson""s diseases, multiple sclerosis, traumatic encephalopathy, traumatic spondylopathy, etc.), pulmopathy such as fibroid lungs, bone resorption diseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis, hypercalcemia, osteometastasis of cancer etc.), endocrinesthenia such as hyperthyroidism.
It was confirmed by the following experiments that the compounds of the present invention of formula (I) have an inhibitory activity against cysteine protease.
(i) Measurement of Cathepsin K Inhibitory Activity
65 xcexcL of Cathepsin K enzyme reaction buffer (50 mmol/L of 2-(N-morpholino)ethanesulfonate, 2 mmol/L of ethylenediamine tetraacetate (EDTA) and 4 mmol/L of dithiothreitol (DTT) were mixed to adjust to pH 5.5), 5 xcexcL of cysteine protease inhibitor solution of several concentrations, 20 xcexcL of synthesized substrate (t-butyloxycarbonyl-L-alanyl-glycyl-L-prolyl-L-arginine-4-methyl-chromanyl-7-amide) solution of several concentrations and 10 xcexcL of cathepsin K enzyme solution were mixed and the increase of fluorescence intensity when reacted at 37xc2x0 C. was measured (xcex ex (excitation wavelength)=355 nm, xcex em (fluorescence wavelength)=460 nm). As to the substrate and the compound of the present invention, enzyme reactions were carried out in combination of several appropriate concentrations and Dixon plotting was prepared, to define the absolute value of X-coordinate of the intersection point of the graph as Ki value.
It was confirmed that the compound of the present invention of formula (I) had an inhibitory activity more than 50% at 10 xcexcM. For example, the Ki values of inhibitory activity of the compounds of example 3, example 3 (14) and example 31 were 0.17 xcexcM, 0.10 xcexcM and 0.081 xcexcM respectively.
(ii) Measurement of Cathepsin B Inhibitory Activity
10 xcexcL of Synthesized substrate (carbobenzoxy-L-arginyl-L-arginine-4-methyl-chromanyl-7-amide or carbobenzoxy-L-phenylalanyl-L-arginine-4-methyl-chromanyl-7-amide) solution of several concentrations, 10 xcexcL of cysteine protease inhibitor solution of several concentrations, 70 xcexcL of cathepsin B enzyme reaction buffer (mixture of 400 mmol/L in acetic acid, 4 mmol/L EDTA, 8 mmol/L DDT to adjust to pH 5.5) and 10 xcexcL of cathepsin B enzyme solution were mixed and the increase of fluorescence intensity was measured (xcex ex (excitation wavelength)=355 nm, xcexc em (fluorescence wavelength)=460 nm) when reacted at 37xc2x0 C.
It was confirmed that the compound of the present invention of formula (I) had an inhibitory activity more than 50% at 10 xcexcM. For example, the inhibitory activity of the compound of example 10 was 95% at 1 xcexcM.
(iii) Measurement of Cathepsin S Inhibitory Activity
10 xcexcL of synthesized substrate (carbobenzoxy-L-leucyl-L-leucyl-L-arguinine-4-methyl-chromanyl-7-amide) solution and 5 xcexcL of cysteine protease inhibitor solution of several concentrations, 75 xcexcL of cathepsin S enzyme reaction buffer (100 mmol/L of sodium phosphate, 2 mmol/L of EDTA, 2 mmol/L of DTT were mixed to adjust to pH 6.5) and 10 xcexcL of cathepsin S enzyme solution were mixed and the increase of fluorescence intensity was measured (xcex ex(excitation wavelength)=355 nm, xcex em (fluorescence wavelength)=460 nm) when reacted at 37xc2x0 C.
It was confirmed that the compound of the present invention of formula (I) has an inhibitory effect more than 50% at 10 xcexcM. For example, the inhibitory activity of the compound of example 18 was 98% at 1 xcexcM.
(iv) Measurement of Cathepsin L Inhibitory Activity
5 xcexcL of Synthesized substrate (carbobenzoxy-L-phenylalanyl-L-arguine-4-methyl-chromanyl-7-amide or L-prolyl-L-phenylalanyl-L-arguinine-4-methyl-chromanyl-7-amide) solution and 5 xcexcL of cysteine protease inhibitor solution of several concentrations, 80 xcexcL of cathepsin L enzyme reaction buffer (400 mmol/L acetic acid, 4 mmol/L EDTA, 8 mmol/L DTT were mixed to adjust to pH 5.5) and 10 xcexcL of cathepsin L enzyme solution were mixed and the increase of fluorescence intensity was measured (xcex ex (excitation wavelength)=355 nm, xcex em (fluorescence wavelength)=460 nm) when reacted at 37xc2x0 C.
It was confirmed that the compound of the present invention of formula (I) had an inhibitory activity of more than 50% at 10 xcexcM. For example, the inhibitory activity of the compound of example 22(4) was 97% at 1 xcexcM.
(v) Measurement of Calpain Inhibitory Activity
The activity was measured according to the method described in Calcium-depending protease, Seibutsukagaku-Jikkenhou (Biochemistry Experimental Method) Tanpakubunkaikouso (Protease) I, 57 (1993).
(vi) Measurement of Caspase-1 Inhibitory Activity
50 xcexcL of caspase-1 enzyme reaction solution (20 mmol/L of 4-(2-hydroxyethyl)-1-piperazinethanesulfonate-sodium hydroxide buffer pH 7.4, 10 mmol/L of potassium chloride, 1.5 mmol/L of magnesium chloride, 0.1 mmol/L EDTA, 10% glycerol) and 50 xcexcL of cysteine protease inhibitor solution of several concentrations, 50 xcexcL of caspase-1 enzyme solution and 100 xcexcL of synthesized substrate (acetyl-L-tyrosinyl-L-valinyl-L-alanyl-L-aspartic acid-4-methyl-chromanyl-7-amide) solution of several concentrations were reacted at 37xc2x0 C. and the fluorescence intensity was measured (xcex ex (excitation wavelength)=355 nm, xcex em (fluorescence wavelength)=460 nm).
(vii) Investigation in Bone Resorption Inhibitory Activity Using Mouse Calvaria Cultivation System
Mouse neonatal calvaria was cultured in D-minimal essential medium containing cysteine protease inhibitor (mixture of Penicillin G potassium (final concentration 100 U/ml), streptomycin sulfate (final concentration 0.1 mg/ml), bovine serum albumin (final concentration 0.1%), glutamine (final concentration 0.3 mg/ml) in D-minimal essential medium) at 37xc2x0 C. and the calcium concentration in the culture medium was measured.
(viii) Bone Resorption Pit Formation Test Using Rabbit Osteoclast Cells
Osteoclast cells collected from rabbit bones were sowed over slices of bovine cortical bone, ivory or teeth of toothed whale and were cultured at 37xc2x0 C. in xcex1-minimal essential medium containing final concentration 5% of fetal bovine serum and various concentrations of cysteine protease inhibitor. The pits formed on the slices by the osteoclast cells were observed and at the same time type-I collagen C-terminal telopeptide (CTx) concentration in culture medium was measured.
(ix) Investigation of Immune Reaction Inhibitory Effect Using Antigen-Sensitized Mouse Spleen Cells
Spleen cells were collected from mice sensitized by ovalbumin (OVA) several times. Inhibitory effect of cysteine protease inhibitors against immune response induced by OVA stimulus was investigated, using cytokine concentration and immunoglobulin concentration in culture solution as indicators.
(x) Investigation in Inhibitory Effect Against Bone Resorption Using the Rat PTH Hypercalcemia Model
The effect of cysteine protease inhibitor (compulsory oral administration, intraperitoneal administration) on bone resorption which was promoted by intravenous administration of parathyroid hormone (PTH) solution (30 xcexcg/ml) was investigated in rats, using calcium concentration in blood as an indicator.
(xi) Studies on Bone Resorption Inhibitory Effect Using TPTx Rat PTHrP-Induced Hypercalcemia Model
The effect of cysteine protease inhibitor (compulsory oral administration, intraperitoneal administration) on bone resorption, promoted by subcutaneous administration of parathyroid hormone related peptide (PTHrP) to a fasting rat (thyroparathyroidectomized; TPTx) was investigated, using calcium concentration in blood as an indicator.
Toxicity
The toxicity of the compounds of the present invention is very low and therefore it was confirmed that the compounds are safe for pharmaceutical use.
Industrial Applicability
Application to Pharmaceuticals
The compound of formula (I) of the present invention has an inhibitory activity against cysteine proteases, and therefore it is useful as an agent for the prophylaxis and/or treatment of inflammatory diseases (periodontitis, arthritis, inflammatory bowel diseases, infectious diseases, pancreatitis, hepatitis, glomerulonephritis, endocarditis, myocarditis, etc.), diseases induced by apoptosis (graft versus host diseases, rejection of an organ transplantation, acquired immune deficiency syndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia, hairy cells leukemia, spondylopathy, disorders of respiratory apparatus, arthritis, HIV or HTLV-1 related diseases such as uveitis, virus-related diseases such as hepatitis C, cancer, collagenosis (systemic lupus erythematosus, rheumatoid arthritis, etc.), ulcerative colitis, Sjoegren""s syndrome, primary biliary cirrhosis, spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, autoimmune diseases such as insulin dependent (type I) diabetes, diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome, periodic thrombocytopenia, aplastic anemia, spontaneous thrombocytopenia, disseminated intravascular coagulation (DIC), etc.), hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) or hepatitis medicamentosa and cirrhosis, dementia such as Alzheimer""s diseases and Alzheimer""s senile dementia, cerebrovascular injury, nerve degeneration diseases, adult acute respiratory distress syndrome, infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma, arteriosclerosis, all kinds of lusus naturae, nephropathy, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy, etc.), diseases induced by disorders of immune response (graft versus host diseases, rejection of an organ transplantation, allergic diseases (bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis, diseases induced by house dusts, irritable pneumonia, food allergy, etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases (insulin-dependent (type I) diabetes, systemic lupus erythematosus, Hashimoto""s diseases, multiple sclerosis, etc.), desease by decomposing various proteins which compose the organism (myodystrophy, cataract, periodontitis, hepatocyte desease by bile acid such as cholestatic cirrhosis, etc.), decomposition of alveolus elastica such as pulmonary emphysema, ischemic diseases (brain ischemia, brain disorders by ischemic reperfusion, myocardial infarction, ischemic hepatopathy, etc.), shock (septic shock, systemic inflammation response syndrome, endotoxin shock, acidosis, etc.), circulatory system disorders (arteriosclerosis, restenosis after percutaneous transluminal coronary angioplasty (PTCA), etc.)), blood coagulation disorders (thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignant tumor, acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC), parasitic diseases such as malaria, nerve degenerative diseases (Alzheimer-type dementia, Huntington""s chorea, Parkinson""s diseases, multiple sclerosis, traumatic encephalopathy, traumatic spondylopathy, etc.), pulmopathy such as fibroid lungs, bone resorption diseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis, hypercalcemia, osteometastasis of cancer etc.), endocrinesthenia such as hyperthyroidism.
For the purpose described above, the compounds of formula (I), of the present invention, non-toxic salts thereof, acid addition salts thereof or hydrates thereof may normally be administered systemically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person at a time are generally from 1 mg to 1000 mg, by oral administration, up to several times per day, and from 1 mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration for from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases wherein doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered in the form of, for example, solid compositions, liquid compositions or other compositions for oral administration, injections, liniments or suppositories for parenteral administration.
Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules.
Capsules include hard capsules and soft capsules.
In such solid compositions, one or more of the active compound(s) may be used as a dosage form, as is normal practice, to admix with excipient (e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch), combining agents (hydroxypropyl cellulose, polyvinyl pyrrolidone or magnesium metasilicate aluminate), disintegrating agents (e.g. cellulose calcium glycolate), lubricating agents (e.g. magnesium stearate), stabilizing agents, agents to assist dissolution (e.g. glutamic acid or asparatic acid)and the like. The agents may, if desired, be coated with coating agents (e.g. sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. Further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid compositions for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs. In such compositions, one or more of the active compound(s) are dissolved, suspended or emulsified in diluent commonly used (e.g. purified water, ethanol or mixture thereof). Furthermore, such liquid compositions may also comprise wetting agents or suspending agents, emulsifying agents, sweetening agents, flavouring agents, perfuming agents, preserving agents buffer agent etc.
Injections for parenteral administration include solutions, suspensions, emulsions and solids which are dissolved or suspended to use at a time to use. One or more of the active compound(s) in injections are dissolved, suspended and emulsified in a solvent. The solvents are, for example, distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol such as ethanol or mixture thereof. Moreover the injections may also include stabilizing agents, agents to assist dissolution (e.g. glutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)), suspending agents, emulsifying agents, soothing agents, buffer agents, preserving agents, etc. They are sterilized in the last process or manufactured and prepared by sterile procedure. They may also be manufactured in the form of sterile solid compositions such as freeze-dried one and they may be sterilized or dissolved to use in sterile distilled water for injection or some other solvents immediately before use.
Other compositions for parenteral administration include liquids for external use, and ointment, endermic liniments, inhale, spray, suppositories for rectal administration and pessaries for vaginal administration which comprise one or more of the active compound(s) and are prescribed by methods known per se.
Spray compositions may comprise additional substances other than diluents: e.g. stabilizing agents (e.g. sodium sulfite hydride), isotonic buffers (e.g. sodium chloride, sodium citrate or citric acid). For preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or No. 3,095,355 may be used.
The following reference examples and examples illustrate the present invention, but do not limit the present invention.
The solvents in the parentheses show the eluting or developing solvents and the ratios of the solvents used are by volume in chromatographic separations or TLC.
The solvents in the parentheses in NMR show the solvents used in measurement.